PROJECT SUMMARY This application is for a Mentored Research Scientist Career Development Award (K01). The award will provide the candidate with enhanced skills and necessary training to build a research program that investigates the increased burden of depression in autoimmune diseases of the central nervous system (CNS) with a particular focus on multiple sclerosis (MS). People with MS are a markedly higher risk for psychiatric comorbidities, including depression. Estimates of lifetime prevalence of major depression in people with MS reach 50% and are nearly twice that of those with other chronic conditions. Depression is also linked with excess MS-associated morbidity and mortality. However, the specific mechanisms and risk factors driving the increased burden of depression in MS are not well-understood. The goal of the proposed project is to provide the candidate with advanced skills needed to establish an independent program focused on understanding neurobiological mechanisms of depression people with MS that will better inform treatment and prevention strategies in this high- risk population. The composite, comprehensive training plan proposed combines formal coursework, didactic instruction from her mentors, applied hands-on data collection and analysis sessions and attendance at scientific seminars and meetings. Primary training goals include 1) gaining a deeper understanding of depression biology to better inform studies of risk and prevention, 2) experience in the assessment of depression in large population- based research studies, 3) skills in applied structural neuroimaging analysis as tools to better understand neuroanatomical changes as they relate to depressive symptoms. Other training goals involve gaining critical experience in the evaluation of potential risk upstream risk factors for depression in MS. Specifically, the candidate will receive training in sleep and circadian rhythm biology and evaluation, which are two related and biologically plausible contributors to depression in MS. This comprehensive, composite training program will allow the candidate to leverage existing data and infrastructure from a large on-going observational study that has enrolled over 6,554 MS patients across 10-sites. Standardized quantitative 3-Tesla brain MRIs, depressive symptoms and clinical information are acquired at least annually as a part of this study. She will test whether longitudinal changes in specific brain substructure volumes are associated with depressive symptom worsening in people with MS (Aim 1). Further, to advance our understanding of plausible, upstream depression risk factors, she will also test if circadian rhythm disruption and sleep disturbance are potential contributors to depression (possibly mediated through alterations to brain structure) in a subset of local MS PATHS participants (n=100; Aim 2). Taken together, findings from these studies will be derived using a powerful longitudinal design and may provide important insight into understanding how depressive symptoms evolve in people with MS. The data and, importantly, the training garnered from the proposed award will allow the candidate to become an independent investigator with the skills needed to conduct high-quality depression research as it relates to people with MS.